Method for reduction of organic molecules

ABSTRACT

A method for the reduction organic molecules comprising a Ruthenium-Triphosphine complex with aromatic ligands at the phosphors which are ortho or meta substituted.

This application is a U.S. national phase application under 35 U.S.C. of§ 371 of International Application No. PCT/EP2015/052881, filed Feb. 11,2015, the disclosure of which is hereby incorporated by referenceherein.

The present invention relates to a method for reducing organicmolecules, especially by using Ruthenium-Triphosphine-complexes.

In the prior art, e.g. EP 2 653 457 and related applications, methods ofreducing organic molecules by hydrogenation using Ruthenium-Phosphinecomplexes have been disclosed. Although these methods have proventhemselves to be useful, there is a constant need for furtherimprovement and therefore it is an object to provide alternative and/orimproved Ruthenium-Phosphine complexes for the reduction of organicmolecules

This object is achieved in the present invention by a method for thereduction of organic molecules, comprising the step of:

-   -   a) hydrogenating at least one organic molecule in the presence        of a Ruthenium-Triphosphine-complex whereby the        triphosphine-complex comprises at least one aryl and/or        heteroaryl moeity bound to a phosphine which is substituted in        ortho and/or meta position to the phosphine.

The term “hydrogenation” in the sense of the present inventionespecially means and/or includes the reaction of an organic moleculewith molecular hydrogen and/or a source of molecular hydrogen.

The term “organic molecule” in the sense of the present inventionespecially includes or means at least one molecule having a moiety whichis susceptible for reduction via hydrogenation. Suitable moieties mayinclude double or triple bonds (either carbon-carbon or carbon-oxygen orcarbon-nitrogen) or bonds of carbon with a heteroatom like oxygen,nitrogen or sulfur.

Especially interesting organic molecules in this context are carboxylicacids or carbonic acid and their derivatives, including explicitlycarbonic acid derivatives in aqueous environment that would not beconsidered “organic” in the strict sense. In particular, carboxylic acidderivatives include, but are not limited to, the free acids and theirsalts, esters, lactones, acyclic or cyclic anhydrides, amides, lactames,or imides. Carbonic acid derivatives include CO₂ itself, carbonic acidor its salts (bicarbonates or carbonates), acyclic or cyclic organiccarbonates, carbamic acids and their salts, carbamates, urethanes, orureas.

The term “phosphine” in the sense of the present invention especiallymeans and/or includes trivalent phosphororganic compounds, especiallycompounds with the general formula PR¹R²R³, R¹ to R³ being independentfrom each other an organic residue such as e.g. a substituted orunsubstituted alkyl, aryl and/or heteroaryl.

The term “Ruthenium-Triphosphine-complex” especially means and/orincludes a ruthenium complex where in the coordination sphere of theruthenium a trivalent phosphororganic component is present so that abond (may it be a covalent and/or a coordination bond) between theruthenium and the trivalent phosphororganic component is formed at leasttemporarily during the reaction.

The term “Triphosphine-complex” especially means and/or includes acomplex comprising at least organic compound in which three trivalentphosphors are present.

It should be noted that not necessarily all of the phosphines are boundto the Ruthenium during step a). More especially not all of thephosphors may catalytically be involved in the reaction.

The term “at least one aryl moeity bound to a phosphine which issubstituted in ortho or meta position to the phosphine” especially meansand/or includes that the following moiety is present in thetriphosphine-complex:

where at least one of R¹ to R⁴ is not hydrogen (but the other may be)but an organic substituent, preferably selected out of the groupcomprising alkyl, aryl, heteroaryl, cycloalkyl, alkyloxy, aryloxy,alkenyl, perfluoroalkyl, Silyl, SO₃, amine and fluorene.

The term “at least one heteroaryl moeity bound to a phosphine which issubstituted in ortho or meta position to the phosphine” has the samemeaning mutatis mutandis with the same preferred organic substituents.

Surprisingly it has been found that by doing so the efficacy of thecatalyst and/or the tolerance of the hydrogenation can be increased formost applications within the present invention, at least one of thefollowing advantages could be observed:

-   -   The reaction can be performed at lower catalyst concentration    -   The reaction can for some catalysts even be carried out in the        presence of water    -   The reaction can be performed in the presence of solid acidic        additives.    -   The reaction can be carried out at lower temperatures and        pressures    -   The reaction can be performed under continuous-flow conditions

Without being bound to any theory the inventors believe that the orthoor meta substitution at the aromatic system bound to at least one of thephosphors in the complex leads to steric hindrance and thus at leastpartially prevents dimer or heteromer formation of the catalytic activespecies in the hydrogenation reaction. This is consistent with the verysurprising discovery that when some Ruthenium-Triphosphine-complexesaccording to the present invention are used in hydrogenation reactionsthe reaction speed increases with decreasing (and not increasing)catalyst concentration in certain concentration areas.

It should be noted that the inventive Ruthenium-Triphosphine-complex maybe used as a homogenous catalyst or in immobilized form. Also two-phasesystems and phase-transfer-catalysis may be used depending on the actualapplication of the invention. Besides a reaction in batch mode, also acontinuous reaction system is possible.

It should furthermore be noted that the Ruthenium-Triphosphine-complexmay include other ligands such as (but not limited to) carbene, nitrogencontaining-ligands such as amines or amides, phosphites,phosphoamidites, phosphoric ethers or esters etc.

Generic group definition: Throughout the description and claims genericgroups have been used, for example alkyl, alkoxy, aryl. Unless otherwisespecified the following are preferred groups that may be applied togeneric groups found within compounds disclosed herein:

alkyl: linear and branched C1-C8-alkyl,

alkenyl: C2-C6-alkenyl,

cycloalkyl: C3-C8-cycloalkyl,

alkoxy: C1-C6-alkoxy,

alkylene: selected from the group consisting of: methylene;1,1-ethylene; 1,2-ethylene; 1,1-propylidene; 1,2-propylene;1,3-propylene; 2,2-propylidene; butan-2-ol-1,4-diyl;propan-2-ol-1,3-diyl; 1,4-butylene; cyclohexane-1,1-diyl;cyclohexan-1,2-diyl; cyclohexan-1,3-diyl; cyclohexan-1,4-diyl;cyclopentane-1,1-diyl; cyclopentan-1,2-diyl; and cyclopentan-1,3-diyl,

aryl: selected from homoaromatic compounds having a molecular weightunder 300,

arylene: selected from the group consisting of: 1,2-phenylene;1,3-phenylene; 1,4-phenylene; 1,2-naphtalenylene; 1,3-naphtalenylene;1,4-naphtalenylene; 2,3-naphtalenylene; 1-hydroxy-2,3-phenylene;1-hydroxy-2,4-phenylene; 1-hydroxy-2,5-phenylene; and1-hydroxy-2,6-phenylene,

heteroaryl: selected from the group consisting of: furyl, pyridinyl;pyrimidinyl; pyrazinyl; triazolyl; pyridazinyl; 1,3,5-triazinyl;quinolinyl; isoquinolinyl; quinoxalinyl; imidazolyl; pyrazolyl;benzimidazolyl; thiazolyl; oxazolidinyl; pyrrolyl; carbazolyl; indolyl;and isoindolyl, wherein the heteroaryl may be connected to the compoundvia any atom in the ring of the selected heteroaryl,

Unless otherwise specified the following are more preferred grouprestrictions that may be applied to groups found within compoundsdisclosed herein:

alkyl: linear and branched C1-C6-alkyl, more preferred methyl, ethyl,propyl, butyl, t-butyl, sec-butyl, most preferred methyl, sec-butyl andt-butyl.

alkenyl: C3-C6-alkenyl,

cycloalkyl: C6-C8-cycloalkyl,

alkoxy: C1-C4-alkoxy,

alkylene: selected from the group consisting of: methylene;1,2-ethylene; 1,3-propylene; butan-2-ol-1,4-diyl; 1,4-butylene;cyclohexane-1,1-diyl; cyclohexan-1,2-diyl; cyclohexan-1,4-diyl;cyclopentane-1,1-diyl; and cyclopentan-1,2-diyl,

aryl: selected from group consisting of: phenyl; biphenyl; naphthalenyl;anthracenyl; and phenanthrenyl,

arylene: selected from the group consisting of: 1,2-phenylene;1,3-phenylene; 1,4-phenylene; 1,2-naphtalenylene; 1,4-naphtalenylene;2,3-naphtalenylene and 1-hydroxy-2,6-phenylene,

heteroaryl: selected from the group consisting of: furyl, pyridinyl;pyrrolyl and imidazolyl, wherein the heteroaryl may be connected to thecompound via any atom in the ring of the selected heteroaryl,

heteroarylene: selected from the group consisting of: pyridin 2,3-diyl;pyridin-2,4-diyl; pyridin-2,6-diyl; pyridin-3,5-diyl; quinolin-2,3-diyl;quinolin-2,4-diyl; isoquinolin-1,3-diyl; isoquinolin-1,4-diyl;pyrazol-3,5-diyl; and imidazole-2,4-diyl.

According to a preferred embodiment of the present invention, theRuthenium-Triphosphine-complex comprises more than one Phosphine, i.e.that in the coordination sphere of the ruthenium two or more trivalentphosphororganic components are present so that bonds (may it be covalentor coordination bonds) between the ruthenium and the phosphororganiccomponents are formed at least temporarily during the reaction.Especially preferred are Ruthenium-Triphosphine-Complexes.

It should be noted that the present invention is not limited toRuthenium-Triphosphine-complexes where all phosphines are bound to theRuthenium. Actually in many applications of the present invention, thephosphine is used in excess so that also non-bound phosphines arepresent.

Especially preferred for the present invention areRuthenium-Triphosphine-complexes comprising phosphororganic compoundswhere the “bridging” moiety between the phosphors is an alkyl oralkylene moiety whereas the further ligands at the phosphor are aryl orheteroaryl, whereby one of these ligands is substituted in ortho and/ormeta position

According to a preferred embodiment of the present invention theRuthenium-Triphosphine-complex comprises a phosphororganic compoundwhere two or all three phosphors have a aryl and/or heteroaryl moeitywhich is substituted in ortho and/or meta position to the phosphinebound thereto. This has shown to greatly increase the reactionefficiency.

According to a preferred embodiment of the present invention theRuthenium-Triphosphine-complex comprises a phosphororganic compound ofthe following structure

whereby R¹ to R⁶ are independent from each other substituted orunsubstituted aryl or heteroaryl (provided that one of R¹ and R², R³ andR⁴, R⁵ and R⁶ is substituted in ortho and/or meta position to thephosphine) and R⁷ is hydrogen or an organic moeity, preferably alkyl,cycloalkyl or aryl. Especially preferred R⁷ is alkyl, more preferredmethyl or ethyl.

It should be noticed that according to one preferred embodiment of thepresent invention, the Ruthenium-Triphosphine-complex may (prior to thereaction) comprise one or more “volatile” or easy removable ligand whichstabilizes the complex so that it may be handled before the reaction butduring the reaction sequence is replaced by the reactants. Suitableligands are i.e. trimethylmethane, cyclopentadienyl, allyl, methylallyl,ethylene, cyclooctadiene, acetylactonate, acetate or carbon monoxide.

According to a preferred embodiment of the present invention, step a) isperformed under acidic conditions. This has been shown to greatlyincrease the efficiency for most applications within the presentinvention.

The term “acidic conditions” in the sense of the present inventionespecially means and/or includes that during the reaction at leasttemporarily more acid than base is present.

According to a preferred embodiment of the present invention, step a) isperformed under acidic conditions whereby the (initial) concentration ofacid is ≥0.5 to ≤20 times the concentration of Ruthenium (in mol:mol).It has been found that by doing so the reaction speed and the TON can beincreased for many applications within the present invention. Morepreferred the concentration of acid is ≥0.8 to ≤10 times theconcentration of Ruthenium (in mol:mol), yet more preferred ≥1 to ≤2times.

According to a preferred embodiment of the present invention, step a) isperformed under acidic conditions whereby the acid is selected out ofthe group comprising organic or inorganic acids, especially sulfonicacids, especially methanesulfonic acid, trifluormethansulfonic acid,p-toluolsulfonic acid, p-bromobenzosulfonic acid, p-nitrobenzosulfonicacid, sulfuric acid, hydrochloric acid, hydrofluoric acid,trifluoracetic acid, perchloric acid or mixtures thereof. Even morepreferred are acids which provide weak coordinating anions afterdeprotonation, such as bis(trifluoromethane)sulfonimide or mixturesthereof with aforementioned acids. These compounds have proventhemselves in practice.

According to a preferred embodiment of the present invention, step a) iscarried out at a temperature of ≥0° C. to ≤250° C., preferably ≥20° C.to ≤230° C., more preferred ≥60° C. to ≤210° C., even more preferred≥120° C. to ≤200° C. and most preferred at ≥150° C. to ≤180° C. This hasbeen shown to be most efficient for most applications within the presentinvention.

According to a preferred embodiment of the present invention, step a) iscarried out in a dipolar protic or aprotic solvent or in CO₂. Preferredsolvents are ethers, also cyclic ethers such as THF or 1,4-dioxane andCO₂ (either liquid or near or supercritical). CO₂ is for someapplications of the present invention insofar a preferred solvent sinceit is also one of the possible educts.

Of course if the organic molecule to be reduced is liquid (andpreferably the reaction product, too) then according to an alternativepreferred embodiment of the present invention, step a) can be carriedout without any solvent.

According to a preferred embodiment of the present invention, step a) iscarried out at an initial hydrogen pressure of ≥1 bar, preferably ≥10bar and most preferred ≥20 bar. This has been shown to greatly increasethe reaction speed and efficiency for most applications of the presentinvention.

In case CO₂ is a reactand, it is especially preferred that step a) iscarried out at an initial CO₂ pressure of ≥1 bar, preferably ≥5 bar andmost preferred ≥10 bar. This has been shown to greatly increase thereaction speed and efficiency for most applications of the presentinvention, too.

According to a preferred embodiment of the present invention, the methodfurthermore comprises a step a0) to be performed before step a):

-   -   a0) Reacting suitable precursor compounds to form the        Ruthenium-Triphosphine-complex

The precursor can be a salt or complex containing ruthenium, independentof its formal oxidation state. Suitable Ruthenium-containing precursorcompounds include Ru(acac)₃, [Ru(cod)(methylallyl)₂]Ru(nbd)(methylallyl)₂, Ru(ethylene)₂(methylallyl)₂, [(cod)RuCl₂]_(n),RuCl₃, [(PPh₃)₃Ru(H)(CO)Cl] or [(cymanthren)RuCl₂]₂.

Step a0) may be carried out at room temperature or at the sametemperature at step a).

The aforementioned components, as well as the claimed components and thecomponents to be used in accordance with the invention in the describedembodiments, are not subject to any special exceptions with respect totheir size, shape, material selection and technical concept such thatthe selection criteria known in the pertinent field can be appliedwithout limitations.

Additional details, characteristics and advantages of the object of theinvention are disclosed in the subclaims and the following descriptionof the respective Examples which are for illustration of the inventiononly and non-binding.

EXAMPLES

In the following, the following catalyst systems are used, beingreferred to as 1b, 2b (both comparative) and 3b (inventive):

These are made according to the following synthesis scheme:

a) Synthesis of the triphosphine compound:

Ligand R 1a Phenyl 2a 4-Methylphenyl 3a 3,5-dimethylphenyl

b) Synthesis of the Ruthenium-complex

Catalyst R 1b Phenyl 2b 4-Methylphenyl 3b 3,5-dimethylphenyl

These complexes were then used for the hydrogenation of Dimethylitaconate. This model compound was selected since it comprises an alkeneand two ester moieties. Full hydrogenated reaction products are either2-Methyl-1-4-Butanediol (BDO) or the cyclic form 3-Methyotetrahydrofuran(3-MTHF).

In case the hydrogenation is not complete, also Dimethyl methylsuccinate(MBS DME) and/or 2/3-Methyl-γ-Butyrolactone (MGBL) may be found asreaction products.

General Procedure for Hydrogenation Experiments

For the hydrogenation experiments the following general procedure, hereexemplified with Ruthenium(Triphos-Xyl)TMM (1b) was used except wherenoted

A 20 mL stainless steel autoclave with a glass inlet was charged withDimethyl itaconate (3.7258 g, 23.6 mmol), Ruthenium(Triphos-Xyl)TMM (1b)(0.0095 g, 0.01 mmol) and HBTA=Bis(trifluormethylsulfon)imid (0.0028 g,0.01 mmol). It should be noted that the ratio of catalyst/HBTA is alwaysset 1:1 (mol/mol), also when different concentration of catalyst wereused.

The autoclave was sealed, evacuated at high vacuum and refilled withargon at least 3 times and subsequently pressurized with 100 bar H₂ andplaced into a steel cone preheated to 200° C. on a magnetic stir plate.Stirring speed was increased from 0 rpm to 700 rpm within 5 minutes toassure the movement of the stirring bar. Due to the high substrateloading the autoclave needed to be repressurized several times with H₂to 100 bar. After no pressure drop was observable, the autoclave wascooled to 0° C. in an ice bath and was than depressurized to ambientpressure.

Using the general procedure, a series of test hydrogenations were made.The results are listed in the following table (average results out ofthree test reactions):

MBSDME MGBL BDO 3-MTHF Entry Catalyst S/C (in %) (in %) (in %) (in %) 11b 1000 0 2 2 88 2 1b 2000 23 10 0 35 3 2b 1000 2 2 1 93 4 2b 2000 3 1 781 5 3b 1000 2 2 1 94 6 3b 2360 0 0 77 20 7 3b 2000 0 5 1 87

However in the reaction corresponding to entry 7 additionaly 0.2 ml H₂Owere given to the reaction. “S/C” means the ratio of substrate/catalyst(in mol/mol). The further abbreviations are explained above.

It can be seen from the table that when a concentration ofsubstrate/catalyst S/C of 2000 more is used, as in entries 2, 4 and 6the inventive catalyst is clearly superior over the catalyst 1b and also2b. This is quite surprising when taking into account that comparativecatalyst 2b has a substitution in para-position, which is a strongindication that the ortho and/or meta-substitution has a great effect.2b, however is not as efficient as the unsubsituted catalyst 1b.

Furthermore it could be found that even at a much lower concentration(2360 vs. 1000) the inventive catalyst is still active and even hashigher TONs as with the higher concentration, whereas with thecomparative catalyst 1b it is the contrary, here significant non-reducedproducts are found. Catalyst 2b behaves similar as 1b, although here thedifferences are not as strong.

Even when adding significant amounts of water—which would usually beexpected to lead to a complete inertness of the catalyst—the inventivecatalyst was still active and gave only minor amounts of not fullyreduced byproducts, but not of MBSDME as it was the case with the othercatalysts in the absence of water.

The particular combinations of elements and features in the abovedetailed embodiments are exemplary only; the interchanging andsubstitution of these teachings with other teachings in this and thepatents/applications incorporated by reference are also expresslycontemplated. As those skilled in the art will recognize, variations,modifications, and other implementations of what is described herein canoccur to those of ordinary skill in the art without departing from thespirit and the scope of the invention as claimed. Accordingly, theforegoing description is by way of example only and is not intended aslimiting. In the claims, the word “comprising” does not exclude otherelements or steps, and the indefinite article “a” or “an” does notexclude a plurality. The mere fact that certain measures are recited inmutually different dependent claims does not indicate that a combinationof these measured cannot be used to advantage. The invention's scope isdefined in the following claims and the equivalents thereto.Furthermore, reference signs used in the description and claims do notlimit the scope of the invention as claimed.

The invention claimed is:
 1. A method for the reduction of organicmolecules, comprising the step of a) hydrogenating at least one organicmolecule in the presence of a Ruthenium-Triphosphine-complex whereby thetriphosphine-complex comprises at least one aryl and/or heteroarylmoeity bound to a phosphine which is substituted in ortho and/or metaposition to the phosphine, wherein the organic molecules are selectedfrom the group consisting of carbonic acids, derivatives of carboxylicacids and derivatives of carbonic acids, wherein the carboxylic acidderivatives are selected from the group consisting of free acids, saltsof free acids, acyclic anhydrides, cyclic anhydrides, lactames andimides and wherein the carbonic acid derivatives are selected from thegroup consisting of salts of carbonic acid, acyclic organic carbonates,cyclic organic carbonates, carbamic acids and salts of carbamic acids.2. The method according to claim 1, wherein the salts of carbonic acidare bicarbonates or carbonates.
 3. The method according to claim 1,wherein the Ruthenium-Triphosphine-complex comprises a phosphororganiccompound where two or all three phosphors have an aryl and/or heteroarylmoeity which is substituted in ortho and/or meta position to thephosphine bound thereto.
 4. The method according to claim 1, wherein theRuthenium-Triphosphine-complex comprises a phosphororganic compound ofthe following structure

whereby R¹to R⁶ are independent from each other substituted orunsubstituted aryl or heteroaryl provided that one of R¹and R², R³ andR⁴, R⁵ and R⁶ is substituted in ortho and/or meta position to thephosphine, and R⁷ is hydrogen or an organic moiety selected from thegroup consisting of an alkyl moiety, a cycloalkyl moiety and an arylmoiety.
 5. The method according to claim 1, wherein step a) is performedunder acidic conditions.
 6. The method according to claim 1, whereinstep a) is performed under acidic conditions whereby the initialconcentration of acid is ≥0.5 to ≤20 times the concentration ofRuthenium in mol:mol.
 7. The method according to claim 6, wherein stepa) is performed under acidic conditions whereby the acid is a sulfonicacid.
 8. The method according to claim 1, wherein step a) is carried outat an initial hydrogen pressure of ≥1 bar.
 9. The method according toclaim 1, wherein step a) is carried out in a dipolar protic or aproticsolvent or in CO₂.
 10. The method according to claim 7, wherein thesulfonic acid is selected from the group consisting of methanesulfonicacid, trifluoromethanesulfonic acid, p-toluenesulfonic acid,p-bromobenzosulfonic acid, p-nitrobenzosulfonic acid, sulfuric acid,hydrochloric acid, hydrofluoric acid, trifluoroacetic acid, perchloricacid, bis(trifluoromethane)sulfonimide and mixtures thereof.